Food and Drug Administration Substance Registration System Standard Operating Procedure
1 Title: Substance Definition Manual Version: 5c Effective Date: June 10, 2007 Supersedes: Version 5b Approved By: SRS Chemistry Review Committee; FDA Data Standards Council's Vocabulary Standards Working Group
1. Purpose...... 1 a. Defining a Substance ...... 1 b. Modification of Text for Computer Use...... 1 2. Structure Set Up and Layout ...... 3 i. Example: ISOETHARINE ...... 4 3. Molecules Containing Chains...... 4 i. Example: IOPHENDYLATE ...... 4 4. Abbreviations ...... 4 i. Example: ACETOPHENONE...... 4 ii. Example: TRIFLOCIN...... 5 5. Functional Groups ...... 5 a. NITRO Groups and NITRATES ...... 5 i. Example: NITROBENZENE ...... 5 ii. Example: NITRATION...... 5 b. NITROGEN OXIDES ...... 6 i. Example: PYRIDINE 1-OXIDE ...... 6 c. OXIMES...... 6 i. Example: 2-PROPANONE, O-METHYLOXIME...... 6 d. AZIDES...... 6 i. Example: 4-AZIDOBENZAMINE...... 6 e. DIAZO and AZO Compounds...... 6 i. Example: 5-DIAZOURACIL ...... 7 ii. Example: D&C Red No. 33...... 7 f. CYANIDES and ISOCYANIDES ...... 7 i. Example: BENZOYL CYANIDE ...... 7 ii. Example: t-BUTYLISOCYANIDE...... 8 g. SULFOXIDES...... 8 i. Example: ESOMEPRAZOLE ...... 8 6. Mixtures and Salts ...... 8 a. Types of Salts ...... 9 i. Simple Salt Example: MAGNESIUM HYDROXIDE ...... 9 ii. Quaternary Ammonium Compound Example: TETRAETHYLAMMONIUM BROMIDE ...... 9 iii. Salt Formed by Reaction between Organic Base and an Acid Example: GLYCINE HYDROCHLORIDE...... 9 b. Types of Mixtures...... 9 i. Example of an ALL OF Mixture: AMYL NITRILE...... 9 7. Salts and Compounds with Ionic Bonds...... 10 i. Example: SODIUM ACETATE...... 10 ii. Example: POTASSIUM CHLORIDE...... 10 iii. Example: MAGNESIUM PHOSPHATE ...... 10 8. Salts Formed by the Reaction of Ammonia with Acids ...... 11 i. Example: AMMONIUM CHLORIDE ...... 11 ii. Example: AMMONIUM LACTATE ...... 11
1 This guide was formerly titled the Structure Drawing Guide. 9. Salts Formed by the Reaction of Nitrogenous Organic Bases with Acids...... 11 i. Example: TRIETHYLAMINE HYDROCHLORIDE...... 11 ii. Example: AMINOGUANIDINE SULFATE ...... 12 iii. Example: TETRAETHYLAMMONIUM CHLORIDE ...... 12 10. Inner Salts...... 12 i. Example: R-5-CHLORO-2-METHYL-3-(4-SULFOBUTYL)-BENZOTHIAZOLIUM INNER SALT 12 11. Bracket Usage for Salts and Solvates ...... 13 i. Example: 1:1 Compound to Salt Ratio...... 13 ii. Example: 1:2 Compound to Salt Ratio...... 13 iii. Example: LOSOXANTRONE HYDROCHLORIDE (DIHYDOCHLORIDE HEMIHYDRATE) ...... 13 12. Salts Containing a Complex Substance as a Counterion ...... 14 i. Example: FENETHAZINE TANNATE...... 14 13. Substance Of Unknown Or Variable Stoichiometry...... 14 i. Example: VIOMYCIN SULFATE...... 15 14. Partially Ionized Acids ...... 15 i. Example: 5-SULFOSALICYLATE, MONOSODIUM SALT...... 16 ii. Example: Citrate Ion with Single Negative...... 16 iii. Example: MONOSODIUM CITRATE ...... 17 iv. Example: MONOSODIUM GLUTAMATE ...... 17 v. Example: 1H-IMIDAZOLE-4-METHANOL, DIHYDROGEN PHOSPHATE (ESTER), DISODIUM SALT ...... 17 vi. Example: ALENDRONATE SODIUM ...... 17 15. Complex Inorganic and Organic Compounds ...... 18 a. Complex Inorganics...... 19 i. Example: TALC ...... 19 b. Complex Organics...... 19 16. Botanicals ...... 19 i. Example: FENNEL OIL...... 20 17. Foods ...... 20 i. Example ABALONE
Version 5c ii 5/13/2007 i. Example: PHENOL...... 28 e. Oximes...... 28 i. Example: BENZALDOXIME...... 28 f. Guanidines ...... 28 i. Example: 1-PHENYL-3-(4-PHENYL-2-THIAZOLYL) GUANIDINE ...... 28 ii. Example: 1-PHENYL-3-(4-PHENYL-2-THIAZOLYL)GUANIDINE ...... 29 iii. Example: TRAMAZOLINE...... 29 g. Tetrazoles ...... 29 i. Example: 5-(3-PYRIDYL)TETRAZOLE ...... 29 h. Pyrithione ...... 29 i.Thiosulfate and Thiosulfite...... 29 i. Example: SODIUM THIOSULFATE...... 30 j. Purines and Pyrimidines...... 30 i. Example: 6-THIOPURINE ...... 30 ii. Example: 2-THIOURACIL...... 30 k. Tetracyclines ...... 30 i. Example: TETRACYCLINE...... 31 l. Anhydrotetracyclines...... 31 i. Example: CHELOCARDIN HYDROCHLORIDE...... 31 m. Rubicin Antibiotics...... 31 i. Example: ANNAMYCIN...... 32 n. Resonance-Stabilized Ions...... 32 i. Example. PEMIROLAST POTASSIUM ...... 32 ii. Example: PHENOBARBITAL SODIUM...... 33 o. Other Types of Tautomerization...... 33 p. Phenolphthalein and Similar Compounds ...... 33 i. Example: PHENOLPHTHALEIN...... 33 ii. Example: PHENOLPHTHALEIN, SODIUM...... 34 21. Stereochemistry ...... 34 a. E and Z Isomerism (Proposed Not Official) ...... 34 i. Example: NITROFURAZONE ...... 35 ii. Example: RIFAPENTINE...... 35 iii. Example CROTAMITON ...... 35 b. General Rules for Tetrahedral Stereochemistry...... 36 i. Example: 4-(R-2-(ETHYLAMINO)-1-HYDROXYETHYL)BENZENE-1,2-DIOL...... 37 ii. Example: PROPOXPHENE ...... 37 iii. Example: MEPIVACAINE ...... 37 iv. Example: SANTONIN ...... 38 v. Example: METHYLPHENIDATE...... 38 22. Representation of Stereochemical Classes ...... 38 a. Completely Defined Enantiomer ...... 39 i. Example: PREDNISOLONE...... 39 b. Racemic Substances (Optically Inactive) or Substances with Undefined or Unknown Stereochemistry ...... 39 1. A single chiral center...... 39 i. Example: ISOPROTERENOL HYDROCHLORIDE ...... 40 ii. Example: DROFENINE ...... 40 iii. Example DOXPICOMINE (-)-isomer absolute configuration undefined...... 40 2. Multiple chiral centers...... 41 i. Example: PENTAZOCINE HYDROCHLORIDE ...... 41 ii. Example: BENZQUINAMIDE ...... 41 iii. Example: SARPICILLIN HYDROCHLORIDE ...... 42 iv. Example: ENISOPROST...... 42 v. Example: HEXESTROL (Meso compound) ...... 43 c. Chiral Substances (Optically Active) with Undetermined Configuration...... 44 i. Example: LEVOPHACETOPERANE HYDROCHLORIDE ...... 44
Version 5c iii 5/13/2007 d. Spiro Compounds ...... 44 i. Example: HEPTELIDIC ACID...... 44 e. Special Stereochemical Cases...... 45 i. Example: (+)-CAMPHENE...... 46 ii. Example: (+)-CAMPHOR...... 46 iii. Example: PENTAZOCINE LACTATE ...... 46 f. Axial chirality ...... 47 i. Example (S)-1,3-DIMETHYLALLENE...... 47 ii. Example ADENALLENE (+/-)...... 48 23. Isotopically Labeled Compounds ...... 48 a. Position of Substitution Known...... 48 i. Example: IODOANTIPYRINE I...... 48 b. Labeled compound with the position of isotopic atom is unknown ...... 48 i. Example: ROSE BENGAL SODIUM, I-131, Position of Substitution Not Specified...... 49 ii. Example: C-14 CHOLESTEROL; Position of Substitution Not Specified...... 49 iii. Example: DEUTERIUM OXIDE...... 49 24. Substituted Glycerine Compounds (Guidance needs to be developed) ...... 49 i. Example: CALCIUM GLYCEROPHOSPHATE...... 49 25. Carbohydrates and Other Saccharides...... 50 i. Example: DEXTROSE...... 50 ii. Example: D-FRUCTOSE ...... 50 iii. Example LACTOSE, ANHYDROUS...... 51 26. Peptides/Proteins...... 51 a. Description Field...... 52 b. Structure Field and Complete Polypeptide/Protein Substance Definitions...... 53 i. Example: COSYNTROPIN...... 53 ii. Example: BIVALIRUDIN...... 54 iii. Example: ENFUVIRTIDE ...... 55 iv. Example: LUTEINIZING HORMONE ...... 55 v. Example: INSULIN HUMAN...... 56 vi. Example: SOMATROPIN...... 57 vii. Example: EFALIZUMAB...... 57 viii. Example: PEGINTERFERON ALFA-2A...... 59 ix. Example. INFLIXIMAB ...... 60 x. Example: TOSITUMOMAB I-131 ...... 61 c. Salts of peptides and proteins: ...... 63 i. Example: INSULIN HUMAN ZINC ...... 63 ii. Example: GONADORELIN ACETATE...... 64 27. Oligonucleotides (Proposed Not official)...... 65 i. Example: DNA sequence d(AGTC) ...... 66 ii. Example: FOMIVIRSEN SODIUM...... 66 28. Polymers (Proposed Not Official) ...... 67 a. Structure Drawing...... 67 b. Description Field ...... 67 i. Example. Low Density POLYETHYLENE...... 69 ii. Example. High Density POLYETHYLENE ...... 70 iii. Example. MICROCRYSTALLINE CELLULOSE...... 71 iv. Example. POWDERED CELLULOSE...... 72 v. Example. CELLULOSE ACETATE...... 74 vi. Example. CELLACEFATE...... 75 vii. Example. POLOXAMER 124 ...... 77 viii. Example. ACRYLONITRILE- BUTADIENE-STYRENE TERPOLYMER ...... 78 ix. Example: PHENOL FORMALDEHYDE RESINS (Condensation polymers) ...... 80 x. Example: NAPTHOL FORMALDEHYDE RESIN...... 81 xi. Example: 6,6-NYLON...... 83 xii. Example:.HEPARIN (Not Official)...... 83
Version 5c iv 5/13/2007 xiii. Example: POLACRILIN...... 86 29. Active Moieties ...... 87 i. Example: ALENDRONATE SODIUM active moiety is ALENDRONIC ACID...... 88 ii. Example: CHELOCARDIN HYDROCHLORIDE active moiety is CHELOCARDIN ...... 88
Version 5c v 5/13/2007 Version 5c vi 5/13/2007 1. Purpose
This guide is used to standardize the entry of substances into the Food and Drug Administration (FDA) Substance Registration System (SRS). The primary purpose of this guide is to prevent duplicate entries of a single substance. Conventions for drawing structures and for organizing the characteristics of substances are included. The guide also provides limited aesthetic guidelines for the structures as they are intended to be shared with other databases and may be used in professional publications. a. Defining a Substance
In the SRS, a substance is defined using two fields: Structure and Identifying Description. The preferred method to define a structure is using a two-dimensional chemical structure. Chemical structures are easily searched and stereochemistry is readily apparent to the user. Many substances cannot be described completely or at all by a single structure or sets of structures; they require other forms of representation. The Identifying Description Field is used for substances that are not easily defined using structures. Data is captured in the Identifying Description Field using a hierarchy of tags. Different classes of substances, such as polymers and peptides, have specific sets of tags used to describe substances. These tags are explained in detail under the topics in which they apply. Tags are also used to provide information that allows the classification of substances that cannot be completely described by the structure alone.2
For chemical substances, the FDA SRS differentiates substances at the molecular level. Different salts and solvates of a drug are defined as different substances. However, different tautomeric forms are considered the same substance. This guide includes conventions for standardizing the representation of tautomers in order to provide the user with a consistent view and to aid in searching. The SRS allows the registration of stereoisomers through the use of wedge bonds, the chiral flag and Identifying Description tags. Duplicate structures are permitted in the SRS only if the Identifying Description Fields differentiate the substances.
Substances can be mixtures of other substances. Mixtures that contain greater than ten chemically defined substances are considered complex substances and chemical structures are not drawn. Substances that form non-covalent interactions with other added substances are not new substances or mixtures of substances; they are defined as separate substances. Mixtures are either related compounds or compounds that are isolated together. Examples: Beta-cyclodextrin complexed with nicotine is described in the SRS system as two separate substances and is not considered a new substance (nor is it treated as a mixture). Synthetic conjugated estrogens are considered a mixture since the substances are closely related to one another.
The Description Field is used to add additional information about a substance or to describe substances for which a structure is not drawn. The Description Field is tagged with xml tags that are defined throughout the guide.3 The Description Field is part of a substance definition and the combination of Structure and Identifying Description must be unique for a given substance. If multiple sets of description tags are used to define a substance the order of the set of tags are alphabetical according to the primary tag of the set (i.e.
BOTANICAL COMPLEX_SUBSTANCE
FOOD NUCLEIC_ACID POLYMER PROTEIN STEREOCHEMISTRY b. Modification of Text for Computer Use
2 Examples in this document include the Identifying Description field only when they contain data. 3 XML stands or Extended Markup Language and is a computer format used for internet pages.
The rules listed below are used both for Chemical Names, that are both synonyms and preferred terms and the Identifying Description Field.
a. Convert text to uppercase.
Benzene
becomes
BENZENE
b. Convert square brackets, [ and ], and braces, { and }, to parentheses, ( and ).
4H-[1,3]oxathiolo[5,4-b]pyrrole
becomes
4H-(1,3)OXATHIOLO(5,4-B)PYRROLE
c. Spell out Greek letters. Delimit the letter's name with periods. androstan-17-one, 3-hydroxy-, (3α,5α)-
becomes
ANDROSTAN-17-ONE, 3-HYDROXY-, (3.ALPHA.,5.ALPHA.)-
d. Convert an arrow, →, to the two character sequence hyphen/greater than sign, ->.
D-Glucose, O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D-glucopyranosyl-(1→4)-O-α- D-glucopyranosyl-(1→4)-
becomes
D-GLUCOSE, O-4,6-DIDEOXY-4-(((1S,4R,5S,6S)-4,5,6-TRIHYDROXY-3- (HYDROXYMETHYL)-2-CYCLOHEXEN-1-YL)AMINO)-.ALPHA.-D-GLUCOPYRANOSYL- (1−>4)-O-.ALPHA.-D-GLUCOPYRANOSYL-(1−>4)-
e. Do not use the stereochemical descriptors d and l (for dextro and levo). Replace d with (+), l with (-), and dl with (+/-).
Camphor, d-
becomes
CAMPHOR, (+)-
f. Represent primes using single quotes. Do not use double quotes.
' is used for a single prime. '' is used for a double prime
Version 5c 2 5/13/2007 ''' is used for a triple prime '''' is used for a quadruple prime
Technetium-99Tc, chloro[bis[(1,2-cyclohexanedione oxime oximato-κO)(1-)][[1,2-cyclohexanedione (oxime-κO)oximato](2- )]methylborato(2-)-κN,κN',κN'',κN''',κN'''',κN''''']-, (TPS- 7-1-232'4'54)-
becomes
TECHNETIUM-99TC, CHLORO(BIS((1,2-CYCLOHEXANEDIONE OXIME OXIMATO-.KAPPA.O)(1-))((1,2-CYCLOHEXANEDIONE (OXIME- .KAPPA.O)OXIMATO)(2-))METHYLBORATO(2-)- .KAPPA.N,.KAPPA.N',.KAPPA.N'',.KAPPA.N''',.KAPPA.N'''',.KAP PA.N''''')-, (TPS-7-1-232'4'54)-
g. Enter superscripts using the term "SUP" separated from the other descriptors by a space. Place "SUP" and the superscripted information in parentheses.
1,3,5,7-Tetraazatricyclo[3.3.1.13,7]decane
becomes
1,3,5,7-TETRAAZATRICYCLO(3.3.1.1(SUP 3,7))DECANE
h. Subscripts are entered using the term "SUB" separated from the other descriptors by a space. "SUB" and the subscripted information are placed in parentheses.
(15R)-15-methylprostaglandin E2
becomes
(15R)-15-METHYLPROSTAGLANDIN E(SUB 2)
i. Convert (±) to (+/-).
1,2-Benzenediol, 4-[1-hydroxy-2-[(1-methylethyl)amino]butyl]-, hydrochloride, (R*,S*)- (±)-
becomes
1,2-BENZENEDIOL, 4-(1-HYDROXY-2-((1-METHYLETHYL)AMINO)BUTYL)-, HYDROCHLORIDE, (R*,S*)-(+/-)-
j. Convert superscript on radioisotopes to normal text in front of atom symbol 131I becomes 131I. This is an exception to the superscript rule above.
2. Structure Set Up and Layout
Version 5c 3 5/13/2007 Structures are drawn using the landscape format. Atoms should not overlap when hydrogens are displayed on terminal carbon atoms and on heteroatoms. When using MDL software, terminal hydrogens and hydrogens on heteroatoms are not drawn but are displayed when the option is set to hetero-, terminal.4
i. Example: ISOETHARINE
CH3 OH O NH CH3 N CH OH 3 O OH O
Correct Hydrogens Displayed Incorrect Hydrogens Not displayed
3. Molecules Containing Chains
Each atom in a substance containing a long chain is explicitly drawn. Brackets containing repeating units are not used for substances other than polymers and simple salts.5
i. Example: IOPHENDYLATE
I I O
OCH3 O CH3 8 CH CH O 3 3
Correct Incorrect
4. Abbreviations
Abbreviations for chemical groups, such as acetyl, ethyl, isopropyl, methyl, and phenyl, are not used. Explicitly draw each non-hydrogen atom of every chemical group.
i. Example: ACETOPHENONE
4 When the structure is displayed with a 1-cm bond length and a 12 pt arial font. 5 Polymers typically do not have a defined number of repeating units but a range of repeating units. See section 27 on Polymers.
Version 5c 4 5/13/2007
O
O CH3
Ph Me Correct Incorrect
Condensed groups, such as CO2H, COOH, NO2, SO3H, and CF3, are not used. Explicitly draw each atom and bond.
ii. Example: TRIFLOCIN
O OH F CO H F H H 2 N F C N F 3 N N
Correct Incorrect
5. Functional Groups a. NITRO Groups and NITRATES
Nitro groups and nitrates are drawn with a positive charge on the nitrogen and a negative charge on one of the oxygens. They are not drawn with five bonds to the nitrogen.
i. Example: NITROBENZENE
O O + N N O O
Correct Incorrect
ii. Example: NITRATION
O O
+ N N O O O O
Correct Incorrect
Version 5c 5 5/13/2007 b. NITROGEN OXIDES
Nitrogen oxides are drawn with a positive charge on the nitrogen and a negative charge on the oxygen.
i. Example: PYRIDINE 1-OXIDE
O O + N N
Correct Incorrect
c. OXIMES
Oximes are drawn without a charge on any atom.
i. Example: 2-PROPANONE, O-METHYLOXIME
O N CH3
CH CH 3 3
d. AZIDES
The azido group is drawn with all three nitrogen atoms in a straight line. The terminal nitrogen has a negative charge and the middle nitrogen has a positive charge.
i. Example: 4-AZIDOBENZAMINE
NH2 NH2 N N + N N N N
Correct Incorrect e. DIAZO and AZO Compounds
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The terminal diazo group is drawn with the carbon bonded to the two nitrogen atoms in a linear configuration. The terminal nitrogen has a negative charge and the middle nitrogen has a positive charge.
i. Example: 5-DIAZOURACIL
N O N O
NH NH + N N N N O O
Correct Incorrect
Diazo or azo dyes are normally thought to exist entirely in an E or trans configuration and are drawn as such unless information is provided otherwise. A Z or cis configuration usually forces the aromatic rings out of the plane and is usually a “high energy” configuration. These dyes are also drawn as diazo and not as hydrazone tautomers.
ii. Example: D&C Red No. 33
O O O O O O O O S S S S O O O O N N NH OH N 2 NH2 O NH + + Na Na 2 2
Correct Incorrect
f. CYANIDES and ISOCYANIDES
Compounds with a cyano or an isocyanide group are drawn with the nitrogen and carbon atoms of the cyano group in line with the attachment atom.
i. Example: BENZOYL CYANIDE
Version 5c 7 5/13/2007
O O N N
Correct Incorrect
ii. Example: t-BUTYLISOCYANIDE
CH 3 CH 3CH 3 3CH + C CH N + 3 CH N C 3
Correct Incorrect
g. SULFOXIDES
The sulfoxide group is drawn in a charge-separated configuration to allow for the assignment of chirality. A single bond is drawn between the sulfur and the oxygen atoms. A negative charge is placed on the oxygen atom and a positive charge on the sulfur atom.
i. Example: ESOMEPRAZOLE
H Chiral H Chiral N O N O + S N S N CH CH 3 N 3 N O CH3 O CH3
CH O CH CH O CH 3 3 3 3
Correct Incorrect
6. Mixtures and Salts
Substances that contain multiple molecules or ions are presented as either a salt or a mixture. For a salt, all the components are stored in a single record. A mixture is represented by two or more substance records that are brought together to define a new substance. The registration system has a module design for entering mixtures. When a mixture is viewed, each component is listed in a table and each substance is displayed separately.
For the SRS, a simple salt is defined as an ionic compound of fixed, undefined, or variable stoichiometry. This includes simple salts, quaternary ammonium compounds, and salts formed by reaction between organic bases and acids.
Version 5c 8 5/13/2007 a. Types of Salts
i. Simple Salt Example: MAGNESIUM HYDROXIDE
2+ Mg OH 2
ii. Quaternary Ammonium Compound Example: TETRAETHYLAMMONIUM BROMIDE
+ 3CH N CH3 Br CH CH 3 3
iii. Salt Formed by Reaction between Organic Base and an Acid Example: GLYCINE HYDROCHLORIDE6
O
2NH ClH OH
b. Types of Mixtures
Three types of mixtures are possible: “ALL OF”, “ANY OF”, and “ONE OF”. An “ALL OF” mixture is used when two or more substances are always present. An “ANY OF” mixture is used when at least one component is present, but there is the possibility that many if not all the components are present. An 'ONE OF' mixture is used when only one of the components is present.
i. Example of an ALL OF Mixture: AMYL NITRILE
6 A salt formed by the reaction of an organic base with an acid is drawn as the organic base and the acid form of the counter ion, not as two ions (for more examples, see section 7 on Salts Formed by the Reaction of Nitrogenous Organic Bases with Acids).
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United States Pharmacopeia (USP) defines Amyl Nitrate as a mixture of the nitrite esters of 3- methyl-1-butanol and 2-methyl-1-butanol.
Mixture Type: “ALL OF”
CH O O 3 CH N 3 CH O O CH 3 3 N
α-Lactose β-Lactose
7. Salts and Compounds with Ionic Bonds
Ionic bonds are drawn by displaying a charge on the appropriate atoms.
i. Example: SODIUM ACETATE
O O O
+ Na (0) CH O Na CH O CH OH Na 3 3 3 Correct Incorrect Incorrect
For simple salts, place the cation on the left and the anion on the right. When the stoichiometry is 1:1, simply place the components next to each other.
ii. Example: POTASSIUM CHLORIDE
+ K Cl
Indicate other stoichiometric ratios by placing brackets around any ion that is repeated. Place the repeat count at the bottom right hand corner of the brackets.
iii. Example: MAGNESIUM PHOSPHATE
Version 5c 10 5/13/2007
O 2+ Mg O P O 3 O 2
8. Salts Formed by the Reaction of Ammonia with Acids
A salt formed by the reaction of ammonia with an acid is represented as the ammonium ion and the conjugate base of the acid.
i. Example: AMMONIUM CHLORIDE
+ NH Cl NH ClH 4 3
Correct Incorrect
ii. Example: AMMONIUM LACTATE
O O
+ NH4 OH OH
O OH NH3 CH CH 3 3
Correct Incorrect
9. Salts Formed by the Reaction of Nitrogenous Organic Bases with Acids
A salt formed by the reaction of a nitrogenous organic base with an acid is represented as the free base and the acid form of the counter ion.
i. Example: TRIETHYLAMINE HYDROCHLORIDE
Version 5c 11 5/13/2007
H + N CH CH3 H3C 3 CH N ClH 3 Cl CH CH 3 3
Correct Incorrect
ii. Example: AMINOGUANIDINE SULFATE
O H O H NH N 2NH N 2 NH OHS O NH2 OH S OH 2 + NH O NH O 2
Correct Incorrect
The nitrogen atom in a quaternary ammonium compound is drawn with a positive charge . iii. Example: TETRAETHYLAMMONIUM CHLORIDE
CH3 CH3
+ CH H CH N 3 N 3
3CH 3CH
CH Cl CH ClH 3 3
Correct Incorrect
10. Inner Salts
Inner salts are substances in which positively and negatively charged groups are contained within the same molecule.
i. Example: R-5-CHLORO-2-METHYL-3-(4-SULFOBUTYL)-BENZOTHIAZOLIUM INNER SALT
Version 5c 12 5/13/2007 Chiral O Cl OH Cl Chiral O S O O S O
+ H H3C N 3CH N
CH S CH S 3 3
Correct Incorrect
11. Bracket Usage for Salts and Solvates
Salts and solvates contain two or more molecular entities in the structure field. If the ratio of the components is 1:1, they are placed side by side. If the ratio is not 1:1, brackets are used to indicate the ratio of the components. Brackets are always labeled with whole numbers or S-text. Brackets are not labeled with fractions. For hemihydrates and similar situations use the ratio with the lowest whole numbers.
i. Example: 1:1 Compound to Salt Ratio
S NH2 Cl H N H N 2
ii. Example: 1:2 Compound to Salt Ratio
Chiral
NH2 O S O CH3 ClH 3CH S O 2 O NH 2
iii. Example: LOSOXANTRONE HYDROCHLORIDE (DIHYDOCHLORIDE HEMIHYDRATE)
Version 5c 13 5/13/2007
H N OH NN ClH OH 4 2
OH O NH OH N H 2
12. Salts Containing a Complex Substance as a Counterion
When a substance consists of a well-defined component and a complex counterion, the resulting salt is treated as a mixture.7 The mixture consists of one record for the well-defined component and one record, for the complex counter ion.
i. Example: FENETHAZINE TANNATE
Mixture Type: “ALL OF”
Fenethazine tannate is drawn as a mixture of fenethazine and a tannic acid. This represents a mixture of a mixture (tannic acid)
CH CH 3 N 3
N
S
FENETHAZINE
Tannic acid: See section 15.
13. Substance Of Unknown Or Variable Stoichiometry
7 For an example of a salt with a well-defined counterion, see section on Salts Formed by the Reaction of Nitrogenous Organic Bases with Acids.
Version 5c 14 5/13/2007
For substances with undefined stoichiometry, enclose the undefined component in brackets. Attach the word “UNDEFINED” to each bracket as S-text.8
For substances with two or more components, the main component is not placed in brackets. Only the minor component, which typically is a solvate or counter ion, is bracketed.
i. Example: VIOMYCIN SULFATE
OH Chiral H N NH OH O O NH O H O N NH HSO OH O NH 2 O NH O UNDEFINED NH NH 2 O H NH2 O H N
OH N NH2 H
14. Partially Ionized Acids
If a molecule contains multiple ionizable groups and is only partially ionized, the group that is the strongest acid is ionized first. The order of ionization for acidic functional groups is listed in the following table in order decreasing acidity:
Functional Group Acidity Table -OSO3H ,–SO3H -OSO2H -SO2H -OPO3H2 -PO3H2 -CO2H Thiophenol - (-OPO3H) - (-PO3H) Phthalimide, CO3H (peracetyl), .alpha.carbon-hydrogen to nitro group -SO2NH2 (sulfonamide)
8 The use of "S-text", which is a text associated with the structure, is used in a limited number of situations. S-text is always attached to generic brackets.
Version 5c 15 5/13/2007 -OBO2H2 -BO2H2 phenol SH (aliphatic) - (-OBO2H) - (-BO2H) Cyclopentadiene -CONH2 (amide) imidazole -OH (aliphatic alcohol) .alpha.carbon-hydrogen to keto group .alpha.carbon-hydrogen to acetyl ester group sp Carbon hydrogen .alpha.carbon-hydrogen to sulfone group alpha.carbon-hydrogen to sulfoxide group -NH2 (amine) benzyl hydrogen sp2-Carbon hydrogen sp3-Carbon hydrogen
i. Example: 5-SULFOSALICYLATE, MONOSODIUM SALT
OH O OH O
+ + OH Na O Na
OOS OOS O OH
Correct Incorrect
Salts of partially ionized acids are drawn with either all of the same functional groups completely ionized or completely unionized. The extent of ionization is sufficient to account for all the counterions (metal ions; non-hydrogen ions) present in a substance. Hydrogen ions from the extended periodic table are added to balance the charges in the substance. The only exceptions to these rules are the case where all the acidic functional groups are equivalent prior to ionization. For these substances, ionization only occurs to the extent necessary to account for all of the counterions. This exception only applies when all of the same functional groups are equivalent. (see ALENDRONATE SODIUM and MONOSODIUM CITRATE).
When a compound contains two or more of the same functional groups that are not equivalent, two or more structures are possible when it is partially ionized.
ii. Example: Citrate Ion with Single Negative
Citric acid contains three carboxylate groups. The two end groups are equivalent; the central one is not.
Version 5c 16 5/13/2007 OOHO OOHO
HOO HOO H
O OH O O
All of the carboxylate groups in citric acid would be ionized and two hydrogen ion superatoms, H+, from the MDL extended periodic table are added to charge balance the structure.
iii. Example: MONOSODIUM CITRATE
OOHO OOHO
+ + O O Na H+ OH OH Na 2 O O O O
Correct Incorrect
iv. Example: MONOSODIUM GLUTAMATE
O O Chiral O O Chiral
O O OH O
+ Na H+ + NH2 NH Na 2 Correct Incorrect
v. Example: 1H-IMIDAZOLE-4-METHANOL, DIHYDROGEN PHOSPHATE (ESTER), DISODIUM SALT
OO OO
H P P N + N + O O Na O O Na H+ 2 2
N N
Correct Incorrect
vi. Example: ALENDRONATE SODIUM
Version 5c 17 5/13/2007 When acidic functional groups are equivalent before ionization, ionization only precedes to the extent necessary to account for all of the counterions. No H+ superatoms are added to the structure.
+ + Na Na O O O O P P OH OH NH 2NH 2 OH O OH OH H+ P P OH OH O OH2 O OH2 3 3
Correct Incorrect
15. Complex Inorganic and Organic Compounds
Tags for Complex Substances
Unpurified or partially purified animal products, plant products that are not botanicals, substances that contain more than 10 active components or chemicals that cannot be represented by a two-dimensional structure are entered using the Identifying Description field. Complex substances can also be mixtures of several well defined active components in a complex matrix of inactive components. The following tags are used to describe complex substances.
Version 5c 18 5/13/2007 multiples. X following a parenthesis represents unknown or variable. Example: Quindecamine acetate which is a dihydrate would have the molecular formula C30_H38_N4.(C2_H4_O2)2.(H2_O)2.
Many inorganic substances exist as complex crystalline or amorphous structures that cannot be easily represented using MDL software. The following is an example of how tags are used for complex inorganic substances.
i. Example: TALC
b. Complex Organics
i. Example: THYROID
16. Botanicals
Botanicals are represented in the SRS solely through the use of the Identifying Description Field which includes the Latin trinomial (genus, species, and variety), the author (e.g. Linnaeus, abbreviated L.), the plant part, and the process (e.g. 'extract'). If only the genus is known, the designation 'SPP' is inserted in the species tags to show general applicability to all species under that genus. If the variety, plant part, or process is unknown or not applicable, then they may be omitted. Latin binomials, trinomials, and authors are validated against accepted entries in the United States Pharmacopeia (USP) or the United States
Version 5c 19 5/13/2007 Department of Agriculture's (USDA) Integrated Taxonomic Information System (ITIS) available at http://www.itis.usda.gov/. All plant parts are validated against listed terms in the Plant Part monograph in the Center of Drug Evaluation and Research (CDER) Data Standards Manual available at http://www.fda.gov/cder/dsm/drg/drg00924.htm. Particular extract types (e.g., 'water', 'ethanol') are not permitted for botanicals that originate from within FDA, but shall be permitted for botanicals that originate from a non-FDA source (e.g., International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), European Medicines Agency (EMEA). When the extract type must be represented, it is inserted prior to the word 'extract' (e.g., 'water extract'). Only the following extract solvents are allowed in SRS botanical nomenclature: ethanol, ether, glycerin, toluene, water, ammonia, methanol, and acetone. All plant-derived complex substances would be considered a botanical. Any characterized substances that are present, or are possibly present, in a botanical are purposely excluded from SRS botanical definition.
i. Example: FENNEL OIL
17. Foods
Food indexing is based on the LanguaL international thesaurus for the description of foods. Information on LanguaL may be found at http://www.langual.org
Authoritative sources for information on foods are: Herbst, Sharon Tyler. FOOD LOVER'S COMPANION: COMPREHENSIVE DEFINITIONS OF OVER 6000 FOOD, DRINK, AND CULINARY TERMS .Third Edition. Hauppauge, NY: Barron's Educational Series, c.2001.
Version 5c 20 5/13/2007 US Department of Agriculture Food Safety Inspection Service (FSIS) FACT SHEETS http://www.fsis.usda.gov
Every food should be indexed with as much detail as is given in the food name. This might include extent of heat treatment, cooking method, or preservation method. Every food substance/ingredient must have a unique string of LanguaL codes in order to be assigned a UNII code.
The Substance Registration System indexes only food substances/ingredients, not food products (also known as "finished foods"). Examples of food substances/ingredients are "milk", "egg", "pineapple", or "cherry". Examples of food products are "eggnog" or "fruitcake". Food substances/ingredients are the building blocks for food products. Thus, "peanut", "salt", and "sugar" would be indexed in the SRS but "peanut butter" would not.
It is possible that a food may already be in the dictionary as a complex substance or botanical; an example would be some vegetable oils or some seeds or spices. For foods originating from plants it may also be worthwhile to check the description field for all substances of the same genus to determine if the food has already been entered as a complex substance. To obtain the genus of a plant, the United States Department of Agriculture's (USDA) Integrated Taxonomic Information System (ITIS), available at http://www.itis.usda.gov/, should be used. It can be searched by common name. Care should be taken to ensure that the complex substance or botanical refers to the same part of the plant that the food is derived. If the food is already entered as a complex substance or botanical the food tags should be added to the existing entry.
The following tags are used to define foods:
Version 5c 21 5/13/2007
Version 5c 22 5/13/2007
iii. Example SQUID, BOILED
18. Coordination compounds or complexes (Draft Proposed)
Version 5c 23 5/13/2007 Coordination compounds are defined using the structure field and S-Text which is associated with the bracket enclosing the coordination compound. In cases where it is customary to use a coordination or dative bond, a single bond is drawn and the valence of the coordinating atom is adjusted as necessary.9 The coordination compound is placed in brackets and the brackets labeled using S-Text with a polyhedral descriptor. Polyhedral descriptors are described in the Chemical Abstracts Service (CAS) Index guide.
i. E xample: PLATINATE(2-), TETRACHLORO-, DIPOTASSIUM , (SP-4-1)-
SP-4-1 Cl
+ 2+ K Cl Pt Cl 2 Cl
The brackets and polyhedral descriptor are required to differentiate two isomers that differ only in their configuration around the central atom. The placement of ligands around the central atom is for aesthetic purposes only—MDL software does not provide a mechanism for indicating stereochemistry around the central atom.10 The polyhedral descriptor is added using S-Text and is placed next to the upper right hand corner of the brackets. The S-text field FDAREG_SGROUP is used to store the bracket information .
ii. Example: CISPLATIN and TRANSPLATIN
SP-4-2 (IV) SP-4-1 (IV) NH NH3 3 2+ 2+ (IV) Cl Pt Cl Cl Pt NH3 (IV) Cl NH3
Cis Trans
Without the brackets and coordination descriptors, the MDL software would treat these compounds as duplicates.
Wedge bonds are only used for tetrahedral stereochemistry. Tetrahedral stereochemistry on ligands is treated the same as in non-coordination compounds. The Chiral flag only applies to tetrahedral stereocenters.
iii. Example: DEXORMAPLATIN
9 The MDL software does not include a coordination bond (dative bond). 10 MDL’s software only handles stereochemistry for the following central atoms: C, N, O, S (sulfate and sulfoxide), P, Si, and pentavalent N and P (3 or 4 attachments with one double bond). Only tetrahedral stereochemistry can be represented.
Version 5c 24 5/13/2007
Chiral OC-6-22 Cl H2 (IV) N Cl
4+ Pt
(IV) N Cl H2 Cl
When the arrangement of atoms and/or the chirality around the central atom is not specified in the source, no polyhedral descriptor is used and no brackets are drawn around the coordination compound.
iv. Example: GADOLINATE(2-), (N,N-BIS)2-(BIS(((CARBOXY-.KAPPA.O)METHYL)AMINO- .KAPPA.N)ETHYL)GLYCINATO(5-)-.KAPPA.N,.KAPPA.O)-, DISODIUM
O
(IV) O O O N
3+ + O O Gd O O Na 2 (IV) (IV) N O N
O
v. Example: IRON SUCROSE (Proposed Not Official)
Both the structure field and Complex Substance tags will be used to describe this colloidal substance.
OH OH OH O O + 3+ 2- OH O Na Fe O OH OH2 2 5 8 3 X OH OH OH OH Y
Version 5c 25 5/13/2007 19. Organometalic Compounds
Carbon to metal sigma bonds are drawn as covalent bonds.
i. Example: 2-.BETA.-CARBOMETHOXY-3-.BETA.-(4- TRIM ETHYLSTANNYLPHENYL)TROPANE
O CH3 Chiral O
CH3
N Sn CH3
CH3 CH 3 a. Nitr ogen, Oxygen, and Fluorine Bonded to Metallic Centers
Nitrogen-metal, oxygen-metal, and fluorine-metal bonds are always treated as ionic bonds.
i. Example: TRIPHENYLTIN HYDROXIDE
+ Sn
OH b. Othe r Nonmetals Bonded to Metallic Centers
The type of bond between metal and nonmetallic elements (excluding nitrogen, oxygen, and fluorine) is determined by the elements position in the periodic table. Transition metal-nonmetal (except mercury) bonds and aluminum-nonmetal bonds are drawn as ionic bonds. The following metals are drawn with covalent bonds to nonmetals: mercury, gallium, germanium, indium, tin, antimony, thallium, lead, bismuth, and polonium.
i. Example: THIMEROSAL
O + O Na + O Na O Hg CH S 3 CH3 S 2+ 2CH Hg Correct Incorrect
Version 5c 26 5/13/2007
20. Tautomerization and Resonance Form Presentation
In most instances, the SRS does not allow the registration of different tautomeric or resonance forms of the same compound. To maintain a more consistent set of structures, use the following conventions.11 a. Proto n-Shift Tautomerization
The following categories include tautomers that interconvert by proton transfer. b. Ke tones
The keto-form is drawn when there is potential keto-enol tautomerism.
i. Example: ACETOPHENONE
O OH
CH3 CH2
Correct Incorrect
c. Carbonyl Compounds
In general, carbonyl compounds that tautomerize are drawn in the form containing the carbonyl group, not th e form containing the hydroxyl group.
i. Example: PHENOBARBITAL
CH CH O 3 O 3 CH O 3 NH N N O N O OH N O H H OH N OH
Correct Incorrect Incorrect
d. Ph enols
Phenols are drawn in the hydroxyl form, not the keto form.
11 When the structure of a compound prevents the preferred tautomer from being formed, the compound is drawn in the alternate form.
Version 5c 27 5/13/2007 i. Example: PHENOL
OH O O
Correct Incorrect Incorrect e. Oximes
Oximes are drawn in the hydroxyl form, not the nitroso form.
i. Example: BENZALDOXIME
OH O N N
Correct Incorrect
f. Guan idines
In acyclic guanidines, the double bond is placed between the central carbon and the least substituted nitrogen.
i. Example: 1-PHENYL-3-(4-PHENYL-2-THIAZOLYL) GUANIDINE
H H N N N
NH S
If all nitrogens have substituents, draw the double bond to the nitrogen with the lowest priority as determined using Cahn-Ingold-Prelog sequence rules.12
12 Cahn-Ingold-Prelog sequence rules are outlined in the following papers: R.S. Cahn, C.K. Ingold and V. Prelog, Angew. Chem. 78, 413–447 (1966) , Angew. Chem. Internat. Ed. Eng. 5, 385–415, 511 (1966); and V. Prelog and G. Helmchen , Angew. Chem. 94, 614–631 (1982) , Angew. Chem. Internat. Ed. Eng. 21, 567–583 (1982). 1996 , 68, 2203
Version 5c 28 5/13/2007 ii. Example: 1-PHENYL-3-(4-PHENYL-2-THIAZOLYL)GUANIDINE
CH3 N
CH3 3CH N N H H
If a guanidine is incorporated into a ring, the double bond is placed inside the ring.
iii. Example: TRAMAZOLINE
N H N
N H
g. Tetrazoles
In tetrazoles, the hydrogen is placed at the one position on the tetrazole ring.
i. Example: 5-(3-PYRIDYL)TETRAZOLE
N N N N N N N N NH H N
Correct Incorrect
h. Pyrithione
Pyrithione and pyrithione salts are drawn in the thiol-nitroxide form, not the thione-hydroxylamine tautomer.
O OH + N SH N S
Correct Incorrect
i.Thiosulfate and Thiosulfite
Thiosulfate and thiosulfite are represented with a sulfur-sulfur single bond and a hydrogen (or negative charge) on the outer sulfur.
Version 5c 29 5/13/2007 i. Example: SODIUM THIOSULFATE
O O + + Na O S S Na O S S 2 2 O O Correct Incorrect j. Purines and Pyrimidines
All purines and pyrimidines are drawn as Watson-Crick like forms with the keto (thione)-tautomer form assumed and a hydrogen atom at the one position in pyrimidines and at the nine position in purines.
i. Example: 6-THIOPURINE
S SH S H N N N NH N NH
N N N N H N N H
Correct Incorrect Incorrect
ii. Example: 2-THIOURACIL
O O OH OH
NH NH N N
N SH N S N SH N S H H
Correct Incorrect Incorrect Incorrect
k. Tetracyclines
Tetracyclines can tautomerize into numerous isomers. In the SRS, tetracylcines are drawn from the following sub-structure:
Version 5c 30 5/13/2007 OH O OH O O OH
NH2
OH HH N CH CH 3 3
i. Example: TETRACYCLINE
OH O OH O O Chiral OH O O O O Chiral OH OH
NH2 NH2
OH OH H H H H OH CH3 N OH CH3 N CH CH CH CH 3 3 3 3
Correct Incorrect
l. Anhydrotetracyclines
5a-6-Anhydrotetracyclines are drawn from the following sub-structure:
OH OH O O
i. Example: CHELOCARDIN HYDROCHLORIDE
OHOH O OO Chiral OHOH O O OH Chiral OH OH 3CH 3CH CH3 ClH CH3 ClH
OH O H H CH NH CH NH 3 2 3 2
Correct Incorrect
m. Rubicin Antibiotics
Version 5c 31 5/13/2007
Antibiotics in the rubicin family are drawn from the following sub-structure:
O
OOH
i. Example: ANNAMYCIN
O OH O OH Chiral OH O O OH Chiral
OH OH
H H O OH O I OH O O I
O OH O OH
CH OH CH OH 3 3
Correct Incorrect
n. Resonance-Stabilized Ions
Tautomers are distinct isomers that interconvert, typically by the migration of a hydrogen atom. The same ion is produced regardless of which tautomer losses a proton. The ion produced has a resonance form that corresponds to each tautomer. Draw the resonance form that corresponds to tautomer that is drawn using the conventions listed above.
i. Example. PEMIROLAST POTASSIUM
Version 5c 32 5/13/2007
When PEMIROLAST POTASSIUM loses a proton to form an anion, the anion has the following two resonance forms:
O O N N NN + K + N N N N K N N
N N
CH CH 3 . 3 Correct Incorrect
The structure on the left is the correct anion to enter as it corresponds to the following PEMIROLAST tautomer:
O H N N
N N N
N
CH 3
The negative charge in the anion and the hydrogen in the free base are both placed at the one position on the tetrazole ring.
When chirality is created in a symmetrical molecule by the loss of a proton, the stereochemistry is not described in either the structure or description field.
ii. Example: PHENOBARBITAL SODIUM
CH O 3 CH O 3
+ Na N + Na NH
O N O H O N O
Correct Incorrect o. Other Types of Tautomerization
Some types of tautomerization involve more than just a proton shift. The SRS software does not recognize these tautomers as the same substance.13 p. Phenolphthalein and Similar Compounds
The cyclic ester is drawn for the neutral compounds. The carboxylic acid salt is drawn for the anion.
i. Example: PHENOLPHTHALEIN
13 The SRS registrars are responsible for ensuring that only one tautomer is entered into the system.
Version 5c 33 5/13/2007 O O OH O OH OH
OH O
Correct Incorrect
ii. Example: PHENOLPHTHALEIN, SODIUM
O + Na O + O Na O OH O
O OH
Correct Incorrect
21. Stereochemistry
MDL software has the capability to represent stereochemistry around a double bond and around certain tetrahedral stereocenters. a. E and Z Isomerism (Proposed Not Official)
Molecules that have a double bond are drawn with the substituents arranged according to the double bond’s stereochemistry. Substances that are known to contain both E and Z isomers are handled as “ALL OF” mixtures.
CH CH 3 3 CH 3CH 3
3CH 3CH
Cis (Z) Trans (E)
Version 5c 34 5/13/2007 If the configuration of the double bond is unspecified or unknown in the source document, it is represented by the MDL double either bond..
i. Example: NITROFURAZONE
O
O N NH2 + N N O H O
Identifying Description
ii. Example: RIFAPENTINE
CH CH Chiral 3CH CH3 3 3 O O OH OH O 3CH OH CH OH 3 3CH NH
H3C O O N N O OH O N CH3
Identifying Description
If a substance is known to be a mixture of Z and E isomers both isomers will be drawn as individual substances and an “ALL OF” mixture will be created to represent the mixture.
iii. Example CROTAMITON
Crotamiton is an “ALL OF” mixture of CIS and TRANS isomers. Both isomers are drawn as separate substances.
Version 5c 35 5/13/2007 Mixture type: “All Of”
CH3 O
N
CH3 CH 3
O
3CH N
CH3 CH 3
b. General Rules for Tetrahedral Stereochemistry
Chiral atoms are indicated by the presence of a solid or dashed wedge bond.14 The wider end of the bond is always drawn away from the chiral center. A solid wedge implies that the group attached to the chiral center is projected towards the viewer coming out of the plane formed by the chiral center. A dashed wedge implies the group is projected behind the plane, away from the viewer.
A hydrogen atom is usually not displayed on a chiral center.15 Their presence is inferred. The MDL software locates this "inferred" hydrogen in the larger angle formed by the central atom and the two substituents that are in the plane of the paper.16
Larger Angle H B A C B A C Smaller Angle
If the substituent with the wedge bond is also in the larger angle, the hydrogen is given the opposite orientation. D D H
B B A C A C
14 Racemates with only one chiral center do not contain wedge bonds at the chiral center. 15 In the examples below, hydrogen atoms are included for clarity. 16 See Appendix A, Chemical Representation in the MDL ISIS™/Base Database Maintenance Manual.
Version 5c 36 5/13/2007
If the substituent with the wedge bond is in the smaller angle, the hydrogen is given the same orientation.
H H
B B = B A C A C A C D D D
The wedge bond is placed in the larger angle whenever possible.
i. Example: 4-(R-2-(ETHYLAMINO)-1-HYDROXYETHYL)BENZENE-1,2-DIOL
OH Chiral H H Chiral OH N OH N CH3 CH3 OH OH OH
Correct Incorrect
If a chiral center has nonhydrogen atoms attached, a solid wedge is drawn to one atom and dashed wedge bond to another atom; the two other atoms are attached to the center using a normal bond
ii. Example: PROPOXPHENE
Chiral
O 3CH O
3CH N CH CH 3 3
When a chiral center is part of a ring, draw the wedge bond(s) to the group(s) outside the ring.
iii. Example: MEPIVACAINE
Version 5c 37 5/13/2007
Chiral Chiral
CH3 CH3 O CH3 O CH3
N N N N H H
CH3 CH3
Correct Incorrect
When a chiral center is located at the junction of two rings, an explicit hydrogen is added to indicate the configuration.
iv. Example: SANTONIN
Chiral Chiral
CH CH H 3 3
CH O 3 3 CH O O O H
CH3 CH3
O O
Correct Incorrect
A wedge bond should not be drawn to an adjacent chiral center. To prevent this from occurring, add an explicit hydrogen or reposition the wedge on a different bond.
v. Example: METHYLPHENIDATE
OO Chiral OO Chiral CH CH H 3 H 3 N N
H
Correct Incorrect
22. Representation of Stereochemical Classes
Substances are classified as follows: (1) enantiomers, (2) racemates, (3) substances with no or partial information about stereochemical orientation and (4) substances which are chiral but the absolute stereochemistry is not known. Substances can have single or multiple stereogenic centers. The following substances are drawn as single substances: (1) racemates, (2) substances which contain no or partial
Version 5c 38 5/13/2007 information on stereochemical orientation and (3) chiral substances where the absolute stereochemistry is not known. Substances that are known to contain several diastereoisomers are drawn as mixtures.
The following tags are used in the Description Field to describe racemic substances and those substances that have unknown or incompletely described stereochemistry. The Substance Registration System (SRS) defines a racemic substance as any substance that contains significant amounts of both enantiomers. A significant amount is 5% of one enantiomer. Substances that contain greater than 95% of a single enantiomer are considered to be a single chiral substance. The Description Field and tags refer to all of the undefined stereochemistry present in a structure or molecular fragment, not to the individual chiral atoms or centers within the structure.
For a chiral molecule in which the configuration of all stereocenters is known, the chiral flag is attached to the structure. The Identifying Description Field does not contain any stereochemistry tags.
i. Example: PREDNISOLONE
OHChiral O
CH3 OH OH
CH3 H
H H
O
Identifying Description is left blank.
b. Racemic Substances (Optically Inactive) or Substances with Undefined or Unknown Stereochemistry
1. A single chiral center
Substances that contain a single chiral atom that is unspecified or known to be racemic are drawn using a regular (non-wedge) single bond . The Identifying Description Field distinguishes the two cases.
Version 5c 39 5/13/2007 A single structure is drawn for a racemate with one chiral center. Wedge bonds are not used. The chiral center is linked to its neighbors by single bonds.17 The
i. Example: ISOPROTERENOL HYDROCHLORIDE
OH
CH3
OH N CH H 3 OH ClH
Identifying Description
A single structure is drawn for substances that contain a single chiral center where the stereochemistry is unknown. The
ii. Example: DROFENINE
O N CH3 O CH 3
Identifying Description
A single structure is drawn containing normal single bonds for substances that are known to be chiral but where the absolute stereochemistry is not defined. The
iii. Example DOXPICOMINE (-)-isomer absolute configuration undefined.
17 In cases where phosphorus is the chiral atom, a double bond may also be present.
Version 5c 40 5/13/2007 N O
O
N CH CH 3 3
Identifying Description
2. Multiple chiral centers
The same tags used to describe substances with a single chiral center are used to describe substances with multiple chiral centers. The tags refer to the entire structure not individual chiral centers. A single structure is drawn for a racemate that contains more than one chiral center and in which the relative configuration of all the centers is known. Wedge bonds are drawn at each stereocenter. A chiral flag is not used in the structure diagram. The
i. Example: PENTAZOCINE HYDROCHLORIDE
CH3
N CH3
CH3 ClH
CH3 OH
Identifying Description
Where there is no information on relative stereochemistry (the synthesis or purification strategy used to prepare the substance is not known) a single structure is drawn that uses normal single bonds at each chiral center and tags in the Identifying Description Field indicate the lack of knowledge. The
ii. Example: BENZQUINAMIDE
2-(acetyloxy)-N,N-diethyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine-3- carboxamide
18 In the literature, a chemical structure drawn in this format may represent a single enantiomer. In the SRS, this structure represents a racemate or a chiral compound in which the absolute configuration has not been determined.
Version 5c 41 5/13/2007 USAN does not indicate the configuration at any of the chiral centers.
O
3CH O O
N CH3 O 3CH N CH3 CH 3 O
Identifying Description
Substances in which the stereochemistry is partially defined consists of a single record in which all known stereochemistry is drawn and normal bonds are used at chiral centers in which the absolute configuration is unknown. The chiral flag is used to indicate that the stereochemistry defined in the drawing is absolute.
iii. Example: SARPICILLIN HYDROCHLORIDE
Methoxymethyl (2S,5R,6R)-6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-3,3-dimethyl-7- oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylate hydrochloride
The Chemical Abstract name provides absolute stereochemistry for all the chiral centers except the 4 position on the imidazole ring. The name does not indicate if this is a single enantiomer or a mixture of diastereomers. All the known chirality is drawn and the chiral flag is used. The tags refer to the chiral atoms in the substance in which the stereochemistry is not defined.
Chiral
O H NH S N CH3 ClH CH N 3 CH CH 3 O 3 CH3 O O O
Identifying Description
Both stereoisomers are drawn as an “ALL OF” mixture for substances known to contain two different diastereoisomers or contain racemic mixtures of two diastereoisomers.
iv. Example: ENISOPROST
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11,16-dihydroxy-16-methyl-9-oxo-, Prosta-4,13-dien-1-oic acid methyl ester, (4Z,11.alpha.,13E)- (+/-)
USAN indicates the relative stereochemistry between all the chiral centers on the cyclopentane ring. The substance contains two diastereomeric racemates and is represented by an “ALL OF” mixture.
O CH O 3
O
3CH OH
CH3 HO
Identifying Description
O CH O 3
O
3CH OH
CH3 OH
Identifying Description
v. Example: HEXESTROL (Meso compound)
MESO-3,4-BIS(P-HYDROXYPHENYL)-N-HEXANE
3CH OH OH CH 3
Identifying Description
Version 5c 43 5/13/2007
c. Chiral Substances (Optically Active) with Undetermined Configuration
This section covers the following: (1) substances that are optically active and that have not been completely characterized and (2) optically active mixtures of diastereomers. These substances with undetermined composition are divided into two groups: (1)substances with more than one chiral center in which the relative configuration of all the centers is known but the absolute configuration is not and (2) substances that contain more than one chiral center in which the configuration of one or more chiral centers is unknown.
i. Example: LEVOPHACETOPERANE HYDROCHLORIDE
The Chemical Abstract name indicates that this compound is chiral and that the absolute stereochemistry is either R,R or S,S. The substance is drawn as an R,R isomer. The
O ClH
3 CH O H H N
Identifying Description
d. Spiro Compounds
Molecules containing two rings joined at a single carbon are called spiro compounds. The atom at the ring junction is connected to four other atoms and may be chiral. When it is chiral, the wedge bonds are placed in a ring. The solid and dashed wedge bonds are placed in the smaller of the two rings whenever possible.
i. Example: HEPTELIDIC ACID
Version 5c 44 5/13/2007
O Chiral O H O
O H
CH CH OH 3 3
e. Special Stereochemical Cases
Due to the algorithm that MDL uses to determine the absolute configuration of a chiral center, caution must be taken when adding wedge bonds19. Two situations in which error can arise are 3-membered rings and bridgehead chiral centers.
The MDL software interprets the following epoxides as enantiomers.
O O 3CH
CH 3
To avoid this problem, the wedge bond is drawn to a group outside the 3-membered ring.
CH3 CH3
O O
3CH 3CH
O O CH3 CH3 CH 3CH 3 CH3 CH3 O O O O CH 3 CH3 O O Correct Incorrect
Molecules with ring systems that contain a bridge are drawn "flattened," not in a 3D perspective. (See Section 21b)
19 See section 21b on the General Rules for Tetrahedral Stereochemistry.
Version 5c 45 5/13/2007
i. Example: (+)-CAMPHENE
CH3 Chiral CH3
CH3 CH3
CH CH 2 2
Correct Incorrect
When there is stereochemistry at the bridgehead, the wedge bond is drawn within a ring, not to an exocyclic atom or group.
ii. Example: (+)-CAMPHOR
CH3 Chiral CH3 Chiral
O O CH3 Chiral CH3 CH3 O CH3 CH3 CH3
CH3 H H
Correct Incorrect Incorrect: Opposite Enantiomer
If two molecular entities in a single structure field contain chiral centers that are not completely defined by the structure field two sets of stereochemistry tags are necessary. The first set of stereochemistry tags refer to the higher molecular weight species. The comments contain the name of the fragment.
iii. Example: PENTAZOCINE LACTATE
Version 5c 46 5/13/2007
The structure field contains the following chemical drawing.
OH OH H3C CH3 O
N CH3
CH3
CH3 HO
The identifying description tags contain the following tags.
MDL database software is unable to recognize chirality resulting from restricted rotation about sp2 hybiridized carbons. As a result, compounds like (S)-1,3-Dimethylallene are not recognized as chiral.20
H
H
Description tags are used to distinguish the stereoisomers. Consult the CAS Index guide for the methodology used to determine R or S chirality.
i. Example (S)-1,3-DIMETHYLALLENE
20 If presented in a journal, this is a valid structure. However, the SRS software is not able to interpret the chirality.
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ii. Example ADENALLENE (+/-)
2NH N N N OH N
23. Isotopically Labeled Compounds a. Position of Substitution Known
When the position of isotopic labeling is known, the compound is drawn with the appropriate isotope at that position.
i. Example: IODOANTIPYRINE I
CH3 N 3CH N
131 O I
b. Labeled compound with the position of isotopic atom is unknown
Version 5c 48 5/13/2007 When a compound is labeled, but the position of the labeled atom is unknown, the label is drawn unattached to the molecule, but linked to an asterisk(s). The substance could be a pure compound or a mixture. It might have more than one label attached.
i. Example: ROSE BENGAL SODIUM, I-131, Position of Substitution Not Specified
I I
O O O + Na 2 I I O
Cl 131 * I O
Cl Cl
Cl
ii. Example: C-14 CHOLESTEROL; Position of Substitution Not Specified
* 14 CH Chiral C 3 CH3 * * CH * 3 H CH3
CH3 CH3
H H
OH
iii. Example: DEUTERIUM OXIDE
Deuterium is represented by the superatom D, an isotopically labeled hydrogen is not searchable in the database.
O D D
24. Substituted Glycerine Compounds (Guidance needs to be developed)
There are a number of substances that contain an ester or ether of glycerine. When no information is available on which hydroxyl group undergoes substitution, it is drawn as an “ANY OF” mixture.
i. Example: CALCIUM GLYCEROPHOSPHATE
Version 5c 49 5/13/2007 The commercial product is a mixture of calcium β- and (+/-)-α-glycerophosphates.
Mixture Type: “ANY OF” Comment [s1]: This is not the best example as this should be an “ALL OF” mixture. OH OH O O 2+ 2+ OH O P O Ca O P O Ca OH O O
25. Carbohydrates and Other Saccharides
Monosaccharide and the terminal sugar in many polysaccharides are in equilibrium between a chain form and one or more cyclic isomers. These saccharides are represented as a single structure. When multiple cyclic forms are possible, the pyranose isomer is depicted. The anomeric carbon on the terminal end of a monosaccharide or polysaccharide is drawn without any indication of chirality unless the anomeric configuration is explicitly specified.
i. Example: DEXTROSE
Dextrose as defined in USP can be either glucose monohydrate or glucose anhydrous, and is drawn as an “ANY OF” mixture.
Mixture Type: “ANY OF” Chiral
O OH OH
OH OH
OH Chiral
O OH OH OH 2
OH OH
OH
ii. Example: D-FRUCTOSE
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Although fructose is a mixture of furanose and pyranose isomers, it is drawn as a single pyranose sugar.
O OH Chiral OH
OH OH
OH
iii. Example LACTOSE, ANHYDROUS
OH O OHChiral
OH OO OH H OH HO OH
OH 26. Peptides/Proteins.
Since most proteins and peptides are inherently heterogeneous, the SRS system will not attempt to capture all aspects of heterogeneity. Heterogeneity can arise from a wide variety of post-translational modifications. The SRS system will only attempt to capture end-group modification (e.g., amidation, acetylation), glycosylation in a general sense, and other modifications that are essential for activity. For example the SRS will capture γ−carboxylation that is essential for enzymatic activity in a variety of clotting factors, but it will not attempt to capture the extent of C-terminal lysine heterogeneity in antibodies. The assignment of a UNII to protein substances does not imply that two substances with the same UNII are either biosimilar or therapeutically equivalent.
Peptides containing three or less amino acid residues are drawn showing all atoms and will not require an entry into the description field. Peptides/proteins containing up to 100 residues will have an entry in the structure field and will be drawn using the standard single letter amino acid abbreviations for standard amino acids.21 All peptides/proteins with well defined sequences that are greater than three amino acids will be described using the description field tags. The SRS description field does not indicate if a peptide/protein was chemically synthesized, naturally derived, or produced using a recombinant expression system. For glycoproteins, the SRS does not indicate the extent of glycosylation - only that a protein is glycosylated and the type of glycosylation in a general sense. The SRS does not indicate the state of aggregation or self-aggregation due to noncovalent interactions. For peptides up to 100 amino acids in length, the structure field indicates intra- or intermolecular disulfide linkages, whereas the description field does not. For protein conjugates, the conjugate is drawn in the structure field (e.g., PEG, toxin) and
21 Peptides and oligonucleotides are an exception to the rule that abbreviations are not used for chemical groups.
Version 5c 51 5/13/2007 includes the first atom of the protein to which it is linked but the protein is described in the description field.
The sequence of a protein or peptide is the most important feature in distinguishing one from another. Prior to entry of a new substance, search the description field using the protein/peptide’s sequence. For monoclonal antibodies sequences outside of the complementarity determining regions (CDR) of the antibody may be common so the entire sequence should be included in the search. An effort should be made to determine information for all of the following fields, particularly when a partial sequence or no sequence is available:
Version 5c 52 5/13/2007 term HUMAN. If the field is blank, the protein is either not glycosylated or if it is not known whether the protein is glycosylated. The extent and sites of glycosylation will not be indicated. The SRS will also not indicate whether glycosylation is biantennary, triantennary etc., or the extent of sialylation. Proteins that contain a different sites or extent of glycosylation are not distinguished from one another and are given the same Unique Identifier (UNII).
b. Structure Field and Complete Polypeptide/Protein Substance Definitions
In the structure field, peptides are displayed with 15 amino acids per line and are divided into groups of five.
i. Example: COSYNTROPIN
Structure Field
NH2 SWYMS E H F R G K VP G KChiral
COOH K R VPR KYV P
Description Field
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In the structure field, amino acids are assumed to be L unless otherwise specified. D-Amino acids are abbreviated using the three letter code preceded by D- (for instance, D-alanine is abbreviated D-Ala).
ii. Example: BIVALIRUDIN
Structure Field
D-Phe PFRPG G GDG NEG E IChiral
COOH P E E Y L
Description Field
C-Terminal amides are abbreviated @-NH2 where @ represents a one letter amino acid code. They are created using the ISIS Draw residue tool. The amino acid is first expanded and the residue portion eliminated. An NH2 is then added. A new residue is then created given the abbreviation @-NH2. N- Terminal acetyl group is handled in a like manner. The new residue is given the abbreviation Ac-@.
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iii. Example: ENFUVIRTIDE
Structure Field
Ac-Y T SQL IEH SL I E S N QChiral
Q ELK NE Q E L E L DKAW
S LWN W F-NH 2
Description field
Other nonstandard amino acids are drawn expanded, showing all atoms, within the peptide chain.
iv. Example: LUTEINIZING HORMONE
5- Pyroglutamate does not have a standard single letter abbreviation and is drawn expanded. The letter X is used in the
Structure Field
Chiral H O N HYRW S GGL P -NH H 2 O
Version 5c 55 5/13/2007 Description field
The SRS software indicates disulfide bonds by placing x-number (e.g. x2) above the cysteine residues.
v. Example: INSULIN HUMAN
Structure Field
x2 x3 x2 NH 2 G I V E Q C C TLS I C S Y Q Chiral
x1 L E N Y C N COOH
x3 NH 2 F V N Q H LSC GVHAEL L
x1 COOH Y L V C G E RTG F F Y P KT
Description field
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Peptides with more than 100 residues are defined using only the description field. There is no entry in the structure field.
vi. Example: SOMATROPIN
Structure Field: Blank
Description field
vii. Example: EFALIZUMAB
Structure Field: Blank
Description field
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viii. Example: PEGINTERFERON ALFA-2A
This substance is described using both polymer and protein tags. When two sets of tags are present the order is alphabetical according to the parent tags. No delimiter is added between the sets of tags. The molecular weight given in the polymer tags is for the polymer portion of the molecule and not the entire molecule. For details on the polymer tags, see section 27 on Polymers.
Structure
O Chiral
O n CH O N 3 H O H N O CH n O N * 3 H O
Description field
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ix. Example. INFLIXIMAB
Structure Field: Blank
Description field
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Radiolabeled Proteins will be handled like other radioactive compounds. If the site of attachment is not known the radioisotope will be drawn in the structure box and linked to an asterisk.
x. Example: TOSITUMOMAB I-131
131I *
Description field
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c. Salts of peptides and proteins:
Because of multiple sites of ionization on most peptides and proteins, peptides and proteins will not be drawn as ionized moieties. Counterions, unless the valency is well defined will be drawn within “GENERIC” brackets and UNDEFINED will be entered as stext associated with the bracket. There will only be one UNII associated with each salt of undefined or variable stoichiometry. Metal salts will be drawn as charged entities. Acid salts such as acetates, hydrochlorides and sulfates will be drawn as uncharged acids. Substances will not be distinguished by the extent of crystallinity, or release characteristics. Prompt Insulin Human Zinc and Extended Insulin Human Zinc will be given the same UNII as Insulin Human Zinc.
i. Example: INSULIN HUMAN ZINC
Structure Field
NH2 G I V E Q C CSTLS I C Y Q Chiral
L E N Y C N COOH
NH2 F V N Q H LSC GVHAEL L
Y L CV G E RTG F F Y P KT COOH
2+ Zn UNDEFINED
Description field
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ii. Example: GONADORELIN ACETATE
Structure Field
Chiral
O H N HGW SY GLPR -NH2 H O
O
OH2 UNDEFINED 3CH OH UNDEFINED
Description field
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27. Oligonucleotides (Proposed Not official)
Oligonucleotides with three or less nucleotides are drawn showing all atoms. Oligonucleotides up to 30 nucleotides long are drawn using a two letter code for the nucleoside and a one or two letter code for the phosphate linkage. The following abbreviations are used: dA = 2-deoxyadenosine, dC = deoxycytidine, dG =2-deoxyguanosine, dT = thymidine, p = (3'-5')phosphoryl linkage, and ps = (3'-5')phosphorothioyl linkage. The phosphate groups in the chain are negatively charged, so the appropriate cation is added in brackets next to the sequence.
Description Field.
Defined tags for nucleic acids.
Version 5c 65 5/13/2007 <3_MODIFICATION> Fifth tag between
Oligonucleotides with more than 30 residues are defined ONLY by descriptions.
i. Example: DNA sequence d(AGTC)
Structure Field
Chiral + 5' dA p dG p dT p dC 3' Na 3
Description Field
Phosphorothioate oligonucleotides are usually a mixture of many diastereomers since the configuration of the phosphorothioate groups is not controlled during synthesis. No wedge bonds are drawn to phosphorothioate groups:
O S ps = P R O O R 1 2
ii. Example: FOMIVIRSEN SODIUM
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Structure Field
5' dG ps dC ps dG ps dT ps dT ps dT ps dG ps dCChiral
+ ps dT ps dC ps dT ps dT ps dC ps dT ps dT ps Na 20 dC ps dT ps dT ps dG ps dC ps dG 3'
Description Field
28. Polymers (Proposed Not Official)
All polymers that contain known repeating units and/or substituents are defined using both structure and description fields. For each polymer as much detail as is available is added to the description field. Polymers that differ by molecular weight (MW) or distribution of molecular weights are considered different polymers. a. Structure Drawing
The structure field contains the smallest repeating unit that results from the polymerization of the monomer. MDL’s structure repeating unit (SRU) brackets, that are labeled with a single capital letter identifier (A, B, C, etc), are used for homopolymers and copolymers. Tags are used in the description field to indicate the orientation of polymerization for both homopolymers and copolymers.
End groups, if known, are drawn and connected to the ends of a polymer. End groups on copolymers that are not definitely connected to a given polymerized monomer are drawn and enclosed in generic brackets labeled END_GROUP using S-Text.
Cross-linking SRUs in copolymers are treated like other repeating units. When substitution on a polymer exists at multiple sites and is incomplete, the substituent is enclosed in generic brackets labeled R# using S- Text. R-groups are numbered in order of decreasing MW. The repeating unit contains an asterisk at the position of potential substitution. The substituent also contains an asterisk at the site of attachment (See examples #v, and vi).
b. Description Field
The description field contains the following tags:
Version 5c 67 5/13/2007 HOMOPOLYMER ISOTACTIC, HOMOPOLYMER SYNTACTIC, HOMOPOLYMER ATACTIC: A polymer that has a single structural repeating unit where tacticity is known. COPOLYMER RANDOM: A polymer represented by multiple structural repeating units where the order of the repeating units is not controlled. COPOLYMER BLOCK: A polymer represented by multiple structural repeating units where blocks of identical repeating units exist. COPOLYMER GRAFT: A polymer represented by multiple structural repeating units where one polymer is attached to the main chain of another polymer. COPOLYMER UNKNOWN: A polymer represented by multiple structural repeating units where no information about connectivity between structure repeating units is known.
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In the description field tags, high and low limit tags either contain product specification limits or limits at the 95% confidence interval if a standard deviation is given (i.e., +/- 2 times the standard deviation). Example: MW of a given polymer is 5000 +/- 500. The
Particle size, percent water, and percent solvent are not distinguishing factors for polymers.
Care must be taken to ensure that two representations of the same polymer are not entered into the SRS. The SRS software allows registration of the two polymers below:
O + 3CH OOSO Na n O O + H3C OOSO Na nO
A SRS register must use substructure searches prior to entering any polymer that has two or more valid representations.
i. Example. Low Density POLYETHYLENE
Structure Field
* A *
Version 5c 69 5/13/2007 Description Field
ii. Example. High Density POLYETHYLENE
Structure Field
* A *
Version 5c 70 5/13/2007 Description Field
iii. Example. MICROCRYSTALLINE CELLULOSE
Degree of polymerization is less than 350.
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OH Chiral O * * O H A OH OH
Description Field
iv. Example. POWDERED CELLULOSE
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Degree of polymerization is less than 2250 and more than 440.
Structure Field
OH Chiral O * * O H A OH OH
Description Field
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v. Example. CELLULOSE ACETATE
Cellulose acetate is defined using the USP criteria. The weight percent of acetate is not less than 29.0 percent and not greater than 44.8. Positions of potential substitution are indicated by an asterisk for both the polymer and the substituent. Hydrogen atoms are not listed but assumed to occupy positions that are not completely substituted. Polymers are drawn to retain as many of the atoms of the polymer as possible.
Structure Field
* Chiral O
O O * * O H A 3CH * O R1 O * *
Correct
* Chiral
O O * * O A * H 3CH O * * R1
Incorrect
Description Field
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vi. Example. CELLACEFATE
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Structure Field
* Chiral O O O O * * * O A H 3CH * OH
O R2 O * O * R1
Description Field
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vii. Example. POLOXAMER 124
Structure Field
OH O OH O O B A B CH 3
Description Field
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viii. Example. ACRYLONITRILE- BUTADIENE-STYRENE TERPOLYMER
Structure Field N * A * * * B * * C
Description Field
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ix. Example: PHENOL FORMALDEHYDE RESINS (Condensation polymers)
Phenol formaldehyde resins are usually three-dimensional network polymers. Only one structure is drawn for each condensation polymer. The polymer structure is simplified with only two positions of substitution indicated. Substitution of the methylene group will either be ortho to the primary functional group or at the position nearest to the primary functional group.
Structure Field
OH
* A *
Description Field
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In cases where symmetrical substitution is not possible the methylene group is attached to the ortho position or to the nearest position of substitution. The polymer attachment site would be at the nearest site on the opposite side of the functional group.
x. Example: NAPTHOL FORMALDEHYDE RESIN
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Structure Field
* OH n *
Description Field
Version 5c 82 5/13/2007 xi. Example: 6,6-NYLON.
Each of the polymerized monomers is fully drawn out and linked together .
Structure Field
O O H N 2NH OH N N A H H O O Description Field
xii. Example:.HEPARIN (Not Official).
When two moieties can substitute on a given atom such as acetyl and sulfate groups on the amino-group of the sugar, both moieties will be drawn as defined repeating units (see B and C below). When the polymeric
Version 5c 83 5/13/2007 moiety and substituents within a bracket have the same overall molecular weight, the repeating unit that has the most positions of potential substitution will be given priority (see A, B below).
O O O * * S OH OH H O * O MOD_1 O O * OH * O n H O O H O * O O OH * O O N S OH O O n H * OH H * O O OH OH NH O * S OH O CH3 MOD_1 C A
O * S OH O MOD_1 O O * OH H O * O * O n O H O OH OH O N S OH * H O B
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xiii. Example: POLACRILIN
Polacrilin is a synthetic polymer consisting of acrylate residues crosslinked with divinylbenzene. The amount of divinylbenzene present is between 2 and 10%. In the structure field, divinylbenzene is represented by the para-moiety even though it is often a mixture of ortho, meta, and para isomers. The following statement “THE CROSSLINKING MOIETY DIVINYLBENZENE IS A MIXTURE OF THE META, ORTHO AND PARA ISOMERS” is placed in the comments. A similar statement is used if the crosslinking agent is a single isomer.
Structure Field
*
* * B * OH O * * A
Description Field
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29. Active Moieties
Active moieties are included in the FDA/USP Substance Registration System (SRS). An active moiety is defined in 21CFR316.3 as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”
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Active moieties will be added to the SRS without regard to the actual charged state of the molecule in-vivo. By convention in the FDA/USP SRS, the active moiety of a hydrochloride salt of a base will be the free base and not the protonated form of the base. Likewise, the active moiety of a metal acid salt will be the free acid. This definition applies when a molecule can be neutralized by addition or loss of a proton. For quaternary ammonium cations that contain pharmacological activity, the active moiety is the charged cation. This ensures there will be only one active moiety for each single drug substance.
Care should be taken to ensure that an ester is not essential for the pharmacological activity of a substance. An active moiety can be contained within either the alcohol or acidic portion of the molecule. The reviewing division within FDA should provide individual guidance for each ester to determine the active moiety or whether an active moiety exists.
i. Example: ALENDRONATE SODIUM active moiety is ALENDRONIC ACID
+ Na O O O OH P P OH OH NH 2NH 2 OH OH OH OH P P OH OH O O 2OH 3
ii. Example: CHELOCARDIN HYDROCHLORIDE active moiety is CHELOCARDIN
OHOH O O O Chiral OHOH O O O Chiral OH OH 3CH 3CH CH3 CH3
OH HCl OH H H CH NH CH NH 3 2 3 2
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